title: Pyrimidine-2,4,6-trione derivatives and their inhibition of mutant SOD1-dependent protein aggregation. Toward a treatment for amyotrophic lateral sclerosis.
abstract: Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease characterized by the progressive loss of motor neurons, leading to muscle weakness, paralysis, and death, most often from respiratory failure. The only FDA-approved drug for the treatment of ALS, riluzole, only extends the median survival in patients by 2-3 months. There is an urgent need for novel therapeutic strategies for this devastating disease. Using a high-throughput screening assay targeting an ALS cultured cell model (PC12-G93A-YFP cell line), we previously identified three chemotypes that were neuroprotective. We present a further detailed analysis of one promising scaffold from that group, pyrimidine-2,4,6-triones (PYTs), characterizing a number of PYT analogues using SAR and ADME. The PYT compounds show good potency, superior ADME data, low toxicity, brain penetration, and excellent oral bioavailability. Compounds from this series show 100% efficacy in the protection assay with a good correlation in activity between the protection and protein aggregation assays. The modifications of the PYT scaffold presented here suggest that this chemical structure may be a novel drug candidate scaffold for use in clinical trials in ALS.
authors.affiliation: Department of Chemistry, Northwestern University, Evanston, Illinois 60208-3113, United States.
authors.forename: Guoyao
authors.initials: G
authors.lastname: Xia
authors.forename: Radhia
authors.initials: R
authors.lastname: Benmohamed
authors.forename: Jinho
authors.initials: J
authors.lastname: Kim
authors.forename: Anthony C
authors.initials: AC
authors.lastname: Arvanites
authors.forename: Richard I
authors.initials: RI
authors.lastname: Morimoto
authors.forename: Robert J
authors.initials: RJ
authors.lastname: Ferrante
authors.forename: Donald R
authors.initials: DR
authors.lastname: Kirsch
authors.forename: Richard B
authors.initials: RB
authors.lastname: Silverman
mesh_terms: D000690:Amyotrophic Lateral Sclerosis / Q000188:drug therapy*; D000818:Animals; D006801:Humans; D008958:Models, Molecular; D050505:Mutant Proteins / Q000737:chemistry* / Q000235:genetics; D009154:Mutation; D016716:PC12 Cells; D055503:Protein Multimerization / Q000187:drug effects*; D020836:Protein Structure, Quaternary; D011743:Pyrimidines / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology* / Q000627:therapeutic use; D051381:Rats; D013482:Superoxide Dismutase / Q000737:chemistry* / Q000235:genetics; D000072105:Superoxide Dismutase-1
chemical_list: D050505:Mutant Proteins; D011743:Pyrimidines; C000606290:SOD1 protein, human; C000606292:Sod1 protein, rat; D013482:Superoxide Dismutase; D000072105:Superoxide Dismutase-1